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Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease

With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-β-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 s...

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Hauptverfasser: Liang, Ting (VerfasserIn) , Liu, Shiru (VerfasserIn) , Dang, Baiyun (VerfasserIn) , Luan, Xiaofa (VerfasserIn) , Guo, Yifan (VerfasserIn) , Steimbach, Raphael R. (VerfasserIn) , Hu, Jiadong (VerfasserIn) , Lu, Long (VerfasserIn) , Yue, Peiyu (VerfasserIn) , Wang, Ruotian (VerfasserIn) , Zheng, Meng (VerfasserIn) , Gao, Jinming (VerfasserIn) , Yin, Xia (VerfasserIn) , Chen, Xin (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 5 September 2024
In: European journal of medicinal chemistry
Year: 2024, Jahrgang: 275, Pages: 1-18
ISSN:1768-3254
DOI:10.1016/j.ejmech.2024.116624
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejmech.2024.116624
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S022352342400504X
Volltext
Verfasserangaben:Ting Liang, Shiru Liu, Baiyun Dang, Xiaofa Luan, Yifan Guo, Raphael R. Steimbach, Jiadong Hu, Long Lu, Peiyu Yue, Ruotian Wang, Meng Zheng, Jinming Gao, Xia Yin, Xin Chen
Beschreibung
Zusammenfassung:With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-β-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.
Beschreibung:Online verfügbar 24 June 2024, Version des Artikel 25 June 2024
Gesehen am 08.01.2025
Beschreibung:Online Resource
ISSN:1768-3254
DOI:10.1016/j.ejmech.2024.116624

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